Primary liver cancer is the common malignant neoplasm in human with high mortality. The tumor usually develops in the presence of continuous hepatic inflammation and epithelial regeneration in the setting of chronic inflammatory liver diseases. Recent studies from our laboratory have shown an important role of the cytosolic phospholipase A21 (cPLA21) and cyclooxygenase-2 (COX-2)-controlled prostaglandin signaling cascade in liver carcinogenesis. Therefore, inhibiting prostaglandin pathway may represent an effective therapeutic approach to disrupt the inflammation, dysplasia and malignant transformation processes. However, the effort for utilizing pharmacological COX-2 inhibitors for liver cancer chemoprevention and treatment in patients has been hindered by the potential cardiovascular side effect associated with long-term use of some COX-2 inhibitors. Thus, there is an urgent and practical need to identify novel and safer therapeutic targets downstream of COX-2, such as those inhibiting prostaglandin E2 (PGE2) signaling, for effective chemoprevention with lesser side effect. In this continuation application, we hypothesize that the interaction between the prostaglandin receptor, EP1, and EGFR/2-catenin is crucial for hepatocarcinogenesis and that simultaneous inhibition of these key molecules may synergistically prevent hepatocarcinogenesis and provide effective anti-tumor therapy. This hypothesis will be evaluated in three specific aims by utilizing complementary approaches of cultured liver cancer cells and animal models of hepatocarcinogenesis. Aim 1 is designed to delineate the interplays between prostaglandin and EGFR/2-catenin signaling pathways in cultured liver cancer cells and in hepatocellular cancer tissues from the cPLA21 and COX-2 transgenic and knockout mice. In Aim 2, mice with overexpression of COX-2 or cPLA21 plus deletion of EGFR or 2-catenin in the liver will be developed to determine hepatic carcinogen-induced tumor development, with the expectation that deletion of EGFR/2- catenin will prevent COX-2 or cPLA21-induced hepatocarcinogenesis. Aim 3 is designed to evaluate the hypothesis that blocking the prostaglandin receptor EP1 with concomitant inhibition of EGFR or 2-catenin may represent an effective and safe therapeutic strategy for the chemoprevention and treatment of liver cancer. The proposed studies are expected to provide important therapeutic implications for the chemoprevention and treatment of human liver cancer.